Nitric oxide (no)-releasing polymers and compounds and uses thereof

Abstract

The invention provides compositions that are NO-releasing polymers or low-molecular-weight NO-releasing compounds. The invention also provides the secondary amine polymers that are the precursors as well as the products of the NO-releasing polymers. The invention provides methods of making the secondary amine polymer precursors and the NO-releasing polymers. The invention provides methods for the nitrosation of low-molecular-weight amines and secondary amine polymers to form the corresponding low-molecular-weight NO-releasing compounds and polymers.

1 . A composition comprising a polymeric secondary amine having formula (I) 
     
       
         
         
             
             
         
       
       wherein P is a polymeric species with a chemical moiety capable of forming a covalent bond with N, and n is an integer greater than about 20, and R 1 , R 2 , R 3 , R 4 , and R 5  are H, F, or NO 2  provided that when R 1 ═F, then R 2 , R 3 , R 4 , and R 5 ═F; and provided that when R 1 ═NO 2 , then R 2 , R 3 , R 4 , and R 5 ═H; provided that when R 5 ═NO 2 , then R 1 , R 2 , R 3 , and R 4 ═H; when R 2 ═NO 2 , then R 4 ═NO 2  and R 1 , R 3 , and R 5 ═H; and when R 3 ═NO 2 , then R 1 , R 2 , R 4 , and R 5 ═H; 
       or having formula (III) 
     
     
       
         
         
             
             
         
       
       wherein x=2 to 12 and n is an integer greater than about 20, and R 6  is NO 2 , CN, CF 3 , or phenyl sulfone; 
       or a combination thereof. 
     
   
   
       2 . The composition of  claim 1 , further comprising a bioactive or therapeutic compound. 
   
   
       3 . A composition comprising a NO-releasing polymer having formula (II) 
     
       
         
         
             
             
         
       
       wherein P, n, R 1 , R 2 , R 3 , R 4 , and R 5  have the same meaning as described above for formula (I);
 formula (IV) 
 
     
     
       
         
         
             
             
         
       
       wherein x, n, and R 6  have the same meaning as described above for formula (III);
 formula (V): 
 or formula (V) 
 
     
     
       
         
         
             
             
         
       
       wherein x=2 to 12 and n is an integer greater than about 20;
 or a combination thereof. 
 
     
   
   
       4 . The composition of  claim 3 , further comprising a bioactive or therapeutic compound. 
   
   
       5 . The composition of  claim 4 , wherein the bioactive agent is chosen from the group consisting of dopamine agonists, decarboxylase inhibitors, and vascular dialators. 
   
   
       6 . A composition comprising an insoluble, reactively inert secondary polymeric amine comprising a member of the group consisting of (1) a polymer having at least one pendant secondary amine group covalently bonded to the polymer, the secondary amine substituted on a substituted or unsubstituted aryl group, and (2) a polymer having at least one diamine monomer having the amine groups substituted on a substituted aryl group; and
 wherein the substituted aryl group is selected from the group consisting of fluoronitrobenzene, difluoronitrobenzene, perfluorobenzene, difluorocyanobenzene, difluoro-trifluoromethylbenzene, and difluoro-phenylsulfoxybenzene.   
   
   
       7 . A composition comprising a NO-releasing polymer comprising a member of the group consisting of (1) a polymer having at least one pendant N-nitrosamine group covalently bonded to the polymer, the N-nitrosamine group substituted on a substituted or unsubstituted aryl group, and (2) a polymer having at least one dinitrosamine monomer having the N-nitosoamine groups substituted on a substituted aryl group. 
   
   
       8 . The composition of  claim 7 , wherein the substituted aryl group is selected from the group consisting of fluoronitrobenzene, difluoronitrobenzene, perfluorobenzene, difluorocyanobenzene, difluoro-trifluoromethylbenzene, and difluoro-phenylsulfoxybenzene. 
   
   
       9 . A method of making NO-releasing polymers comprising:
 (a) reacting a primary amine polymer with a compound selected from the group comprising monofluoroaryl, difluoronitroaryl, perfluoroaryl, difluorocyanoaryl, difluoro-trifluoromethylaryl, and difluoro-phenylsulfoxyaryl compounds to form a secondary polymeric amine; and   (b) nitrosating the secondary polymeric amine.   
   
   
       10 . The method of making NO-releasing polymers of  claim 11 , further comprising:
 (c) storing the NO-releasing polymers at or below about 4° C. in an inert atmosphere.   
   
   
       11 . A composition comprising a soluble NO-releasing compound having formula (VII) 
     
       
         
         
             
             
         
       
       wherein x=5-11. 
     
   
   
       12 . The composition of  claim 11 , further comprising a bioactive or therapeutic agent. 
   
   
       13 . The composition of  claim 12 , wherein the bioactive agent is selected from the group consisting of dopamine agonists, decarboxylase inhibitors, and vascular dialators.